This invention pertains to a novel sustained release delivery form for biologically active peptides and proteins, and to a method for making such material.
Microencapsulation is a technique of enclosing core materials in a polymeric membrane to produce microparticles.
In the pharmaceutical industry, considerable interest has been generated by the use of microparticles as sustained release delivery formulations for naturally occurring and synthetic drugs. Of particular interest is the use of microparticles as delivery mechanisms for regulatory hormones, such as biologically active peptides and proteins. However, many of the methods for making are of limited utility because of the inability of the manufacturing method to encapsulate a subject compound without destroying the biological activity of the encapsulated material.
Other problems with known prior art microparticulate material arise from the fact that generally such material tends to be of unsuitable size for intravenous injection. Such material also tends to agglomerate, thus deleteriously effecting certain important properties of the materials such as dispersibility. Additionally, microparticulate material which is of suitable size for injection may also be captured by the reticulo-endothelial system, which may have deleterious effects on blood clearance of the microparticle shell material and tissue distribution of the encapsulated core material.
Furthermore, some microparticulate formulations which are suitable for encapsulation of bioactive proteins or peptide molecules (e.g. liposome particles) are limited in their capacity to encapsulate core material because they utilize as a core an aqueous solution in which the bioactive material has necesssarily only limited solubility.
A specific type of microparticulate material and a method of making such material is disclosed in U.S. Pat. No. 3,959,457 (of common inventorship and assignment herewith). This material is comprised of the reaction product produced at the inter phase boundary of a finely dispersed emulsion, comprising;
(I) a water immiscible solution of an organic polyfunctional Lewis base in a low boiling point, slightly polar, organic solvent; and
(II) an aqueous solution of a partially hydrophilic, partially lipophilic, polyfunctional Lewis acid.
Microparticles of this type comprise a multiplicity of closed structures formed of lattice-like high molecular weight salt molecules of the Lewis acid and Lewis base, through which the encapsulated core material diffuses. The rate of diffusion is controlled by both the particle or molecular size of the encapsulated compound and by the openness of the lattice or network of molecules comprising the particle walls. The degree of openness of the lattice is controlled by the spacing of reactive sites on the high molecular weight polyfunctional Lewis acids and by the thickness of the particle walls.
In Lewis acid-Lewis base salt microparticles, of the type referred to above, the degree to which peptides and proteins may be encapsulated is limited. Many biologically active peptides and proteins are either insoluble or unstable in polar organic manufacturing solvents of the type typically used in making these microparticles. These solvents tend to denature or otherwise damage the subject peptide or protein, thus diminishing biological activity.